Rozprawy doktorskie: „Total Synthesis, Methodology”

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O'Hora, Paul. "Novel methodology towards the total synthesis of Pseudopterogorgia metabolites". Thesis, Loughborough University, 2013. https://dspace.lboro.ac.uk/2134/13437.

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In 1982, routine screening of the Pseudopterogorgia elizabethae stirred the scientific community by showing the presence of cytotoxic metabolites with antimicrobial activity. Since this discovery a vast amount of research has been conducted in synthesising metabolites of the soft coral. Herein we report the developments towards the synthesis of two metabolites (+)-Erogorgiaene and (+)-Elisabethadione utilising three key reactions in setting up the molecules three chiral centres. The use of asymmetric allylation, oxy-Cope rearrangement and cationic cyclisation was utilised to set up the desired stereocentres from a starting cinnamyl aldehyde. Natural elisabethadione was synthesised in a racemic form as a 2:1 mixture of diastereoisomers at the C-13 stereocentre.

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Varela, Ann. "Application of lithiantion-borylation methodology to alkaloid synthesis : total synthesis of (-) -stemaphylline". Thesis, University of Bristol, 2017. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.730870.

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Gerstenberger, Brian Stephen. "Progress towards the total synthesis of diazonamide A and related new methodology /". Diss., Digital Dissertations Database. Restricted to UC campuses, 2007. http://uclibs.org/PID/11984.

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Stevens, Kiri. "Methodology for the synthesis of NP25302 and other bioactive natural products". Thesis, University of Oxford, 2011. http://ora.ox.ac.uk/objects/uuid:ae18879e-d75e-4280-ba55-1ae08e64034f.

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Total synthesis of the pyrrolizidine alkaloid NP25302: (+)-NP25302 is an unusual vinylogous urea containing pyrrolizidine alkaloid shown to exhibit cell adhesion inhibition. It was envisaged that this natural product could be accessed by a novel 5-endo-dig cyclisation to construct the pyrrolizidine core, and a Curtius rearrangement to install the vinylogous urea motif. This methodology was first tested on a model system, furnishing nor-NP25302 from L-proline in 12 steps and 9% overall yield. The total synthesis of (±)-NP25302 was completed in 9 steps and 26% overall yield from ethyl 2-nitropropionate using similar methodology. Studies into the stereospecificity of the Au(I)-catalysed cyclisation of monoallylic diols: During the synthesis of (+)-isoaltholactone in the Robertson group, the key Au(I)-catalysed cyclisation was observed to occur with some stereospecificity. Further investigations were therefore conducted into the stereochemical outcome of this reaction using stereodefined allylic alcohols, and from the combined results a mnemonic was proposed to predict the stereochemistry of the products of this reaction. Studies into the total synthesis of ascospiroketals A and B: Investigations were conducted into the total synthesis of the recently isolated natural products ascospiroketals A and B. A second generation synthesis was used to construct advanced intermediates 1 and 2.

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Marshall, Laura. "Novel methodology for the synthesis of ¹³C-labelled phenols and its application to the total synthesis of polyphenols /". St Andrews, 2010. http://hdl.handle.net/10023/875.

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Marshall, Laura J. "Novel methodology for the synthesis of ¹³C-Labelled phenols and its application to the total synthesis of polyphenols". Thesis, University of St Andrews, 2010. http://hdl.handle.net/10023/875.

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The base-catalysed reaction of 4H-pyran-4-one with a range of nucleophiles, namely diethyl malonate, ethyl acetoacetate, nitromethane, acetylacetone and ethyl cyanoacetate, was developed as a reliable, high yielding method for the preparation of para-substituted phenols. The methodology was extended to include the use of the substituted pyranones, maltol, 2,6-dimethyl-4H-pyran-4-one and diethyl chelidonate. Reactions were studied using conventional heating methods and microwave irradiation. Microwave irradiation had definite beneficial effects, with improved yields, reduced reaction times and cleaner reaction profiles. The potential of this methodology was examined for the regioselective placement of ¹³C-atoms into benzene rings using ¹³C-labelled nucleophiles or ¹³C-labelled 4H-pyran-4-ones. [3,5-13C₂]4H-Pyran-4-one and [2,6-13C₂]4H-pyran-4-one were prepared from various ¹³C-labelled versions of triethyl orthoformate and acetone. This methodology was applied to the synthesis of [1,3,5-¹³C₃]gallic acid, via the base-catalysed reaction of [3,5-¹³C₂]4H-pyran-4-one with diethyl [2-¹³C]malonate, followed by subsequent transformations to yield [1,3,5-¹³C₃]gallic acid. The preparation of [2-¹³C]phloroglucinol was carried out via [2-¹³C]resorcinol, with regioselective placement of a single ¹³C-atom into the aromatic ring. This was accomplished from non-aromatic precursors, with the source of the ¹³C-atom being [¹³C]methyl iodide. The key step in this synthesis was the introduction of the third hydroxyl group, which was achieved using a modified iridium-catalysed C-H activation/borylation/oxidation procedure. The scope of an existing C-H activation/borylation reaction was modified and expanded to include a range of protected resorcinol derivatives. A catalyst system was developed which allowed high conversion to the intermediate arylboronic acids, followed by oxidation using aqueous Oxone® to yield the corresponding phenols. Finally, to demonstrate the potential of these new methods for application in the synthesis of isotopically labelled natural products and polyphenols, the syntheses of ¹³C-labelled anthocyanins were studied. A route was developed that could be applied to the synthesis of either cyanidin-3-glucoside or delphinidin-3-glucoside. Only the final coupling/cyclisation step to yield the desired anthocyanin targets remains to be carried out.

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Picot, Ondine. "Homoallylation énantiosélective d'aldéhydes par des diènes 1,3. Vers la synthèse de la (-)-spongidepsine". Thesis, Université Paris sciences et lettres, 2020. http://www.theses.fr/2020UPSLS030.

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La (-)-spongidepsine est un cyclodepsipeptide isolé de l'éponge marine Spongia sp. Ce composé présente des activités cytotoxiques et antiprolifératives contre plusieurs lignées cellulaires cancéreuses. Jusqu'à présent, cinq synthèses totales et deux formelles ont déjà été rapportées, toutes comprenant une déconnexion de la (-)-spongidepsine en trois fragments : un acide carboxylique (C1-C5), un alcool bis-homoallylique (C6-C13) et la N-méthyl-phénylalanine. Notre objectif était de développer une synthèse flexible, efficace de la (-)-spongidepsine qui pourrait être utilisée afin d’avoir suffisamment de matière et effectuer des études biologiques et pour la préparation d'analogues. La synthèse du fragment acide a été réalisée selon une des procédures décrites. Pour accéder au fragment C6-C13, une homoallylation énantiosélective, sans précédent, d'aldéhydes par des diènes catalysée par un sel de nickel a été développée. La réaction a été réalisée en utilisant une combinaison de NiCl2avec des phosphoramidites énantio-enrichis, dérivés de BINOL, en présence d'un donneur d'hydrogène, le Et2Zn, et d'un diène 1,3. Une variété d'aldéhydes aromatiques, aliphatiques et α,β-insaturés a été transformée en alcools bis-homoallyliques correspondants avec des rendements et une énantiosélectivité modérés à bons. La méthode a été appliquée avec succès à la synthèse du fragment C6-C13 de la (-)-spongidepsine
-)-Spongidepsin is a cyclodepsipeptide isolated from the marine sponge Spongia sp. This compound exhibitscytotoxic and antiproliferative activities against several cancer cell lines. Until now, five total syntheses and two formal ones have already been reported, all of them including a disconnection of (-)-spongidepsin into three fragments: a carboxylic acid (C1-C5), a bis-homoallylic alcohol (C6-C13) and N-methyl-phenylalanine. Our objective was to develop a flexible, short and scalable synthesis of (-)-spongidepsin that could be used for further biological studies and for the preparation of analogs. The synthesis of the acid fragment was achieved according to reported procedure. To access the C6-C13 fragment, an unprecedented enantioselective nickel-catalyzed homoallylation of aldehydes with dienes was developed. The reaction was performed using a combination of NiCl2 with enantio enriched phosphoramidites derived from BINOL in the presence of a hydrogen donor, Et2Zn and a 1,3-diene. A range of aromatic, aliphatic and α,β-unsaturated aldehydes were transformed into the corresponding bis-homoallylic alcohols with moderate to good yields and enantioselectivity. The method was successfully applied to the synthesis of C6-C13 fragment of (-)-spongidepsin

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Lewis, Simon Eliot. "The decarboxylative Ireland-Claisen rearrangement : methodology studies and approaches to the total synthesis of (-)-suaveoline". Thesis, Imperial College London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.429457.

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Rosset, Isac George. "Diazocetonas α,β-insaturadas como reagentes multifuncionais: aplicação na síntese de alcaloides piperidínicos e pirrolidínicos". Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/75/75133/tde-20052015-101409/.

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p>O primeira parte do trabalho descreve a preparação de um novo reagente de olefinação de HWE para o preparo de diazocetonas α, β-insaturadas com geometria Z e aplicação na síntese de núcleos piperidínicos funcionalizados. Através da otimização da reação de HWE empregando o benzaldeído como aldeído padrão foi possível maximizar a obtenção do isômero Z desejado (92%, Z:E 9:1). As reações-chave para a formação dos núcleos piperidínicos foram a de olefinação de HWE utilizando amino-aldeídos, obtendo-se bons rendimentos e boa seletividade, seguida de uma reação de inserção N-H catalisada por metais. A versatilidade da metodologia foi demostrada com a aplicação na síntese total de um produto natural: (±)-3,4,5-triidroxipiperidina e em estudos visando a síntese de outro produto natural, a (-)-1-deoxi-altronojirimicina. A química das diazocetonas α,β-insaturadas como intermediários avançados foi também empregada na síntese de um outro produto natural, a (±)-preussina. A rota empregada apresentou alta estereosseletividade na reação-chave (Rearranjo de Stevens) e posteriormente na redução da cetona formada com um redutor volumoso (L-selectride), obtendo um rendimento global de 40% em três etapas. Tentou-se também estender a metodologia para o preparo de diazocetonas α,β-insaturadas trissubstituídas, aplicando os reagentes de olefinação em reações com cetonas. No entanto, diversas tentativas foram feitas e não foi obtido as olefinas de interesse.
The first part of this work describes the preparation of a new HWE olefination reagent to prepare diazoketones α, β-unsaturated with Z geometry and its application in the synthesis of functionalized piperidine cores. After the optimization of the HWE reaction using benzaldehyde as a standard it was possible to prepare the desired Z isomer in 92% (Z:E 9:1). The key reaction for formation of the piperidine cores, N-H metal-catalyzed insertion performed to give a yield of up to 70%. The versatility of the methodology was demonstrated by an application to the synthesis of the natural product (±)-3,4,5-triidroxypiperidine and studies in the synthesis of (-)-1-deoxy-altronojirimicine. The chemistry of α, β-unsaturated diazoketones was also employed in the synthesis of another natural product, the alkaloid (±)-preussine. The employed route showed high stereoselectivity in the key-reaction (Stevens Rearrangement) as well as in the subsequent reduction of the formed ketone with a reducing agent (L-Selectride) giving an overall yield of 40%. We also tried to extend the methodology to prepare trisubstituted α, β-unsaturated diazoketones from the reaction with the olefination reagent and ketones. However, after several attempts no fruitful results were abtained.

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Throup, Adam Eric. "Synthetic methodology and application of enamine [2+2] cyclisations for cyclobutane synthesis : development of integrin antagonists as anticancer therapeutics towards a total synthesis of providencin". Thesis, University of Bradford, 2015. http://hdl.handle.net/10454/14411.

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Cyclobutanes represent an underutilised structural feature in medicinal chemistry, partially due to difficulties in forming them in an easy and controlled manner. Herein is described their application to a drug discovery project and development of the enamine [2+2] cyclisation; a straightforward synthesis of functionalised cyclobutanes. A library of 30 cyclobutane based integrin antagonists have been designed and synthesised to explore the SAR around the hit dual β3 integrin antagonist ICT9055. Several of which were shown to be highly potent antagonists inhibiting cancer cell adhesion, migration and invasion while remaining non-toxic. ICT9072 had comparable β3 activity to hit compound ICT9055 but also had activity against αvβ5 and therefore showed greater inhibition of migration of DLD-1 cells. This showed the ability to modify this scaffold for multi integrin antagonism and potential benefit of this. Synthetic studies towards the marine natural product providencin has led to the development of a previously unknown intramolecular enamine [2+2] cyclisation which has been shown to proceed in a diastereoselective manner. This reaction has been applied to the synthesis of a highly functionalised enatiopure cyclobutene suitable for inclusion into the total synthesis. A model furyl cyclobutane has also been synthesised to exemplify the route from the enantiopure cyclobutene through to the furyl cyclobutane fragment of providencin.

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Throup, Adam E. "Synthetic Methodology and Application of Enamine [2+2] Cyclisations for Cyclobutane Synthesis. Development of Integrin Antagonists as Anticancer Therapeutics Towards a Total Synthesis of Providencin". Thesis, University of Bradford, 2015. http://hdl.handle.net/10454/14411.

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Verrier, Charlie. "Développement de nouvelles méthodologies autour du tertbutanesulfinamide et des éthers d'ynols - Vers la synthèse totale d'alcaloïdes de la famille des lycorines". Thesis, Grenoble, 2013. http://www.theses.fr/2013GRENV052/document.

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Le travail présenté dans ce manuscrit s'intéresse principalement à l'étude d'une voie de synthèse visant les dérivés de la lycorine, alcaloïdes encore mal connus mais possédant des activités biologiques très intéressantes. Dans cette optique, une méthodologie impliquant l'addition nucléophile d'acétylures oxygénés sur les sulfinylimines chirales d'Ellman a été développée, permettant la formation de propargylamines oxygénées avec une excellente diastéréosélectivité. L'application de la réaction développée à la synthèse totale n'a pas été possible, l'étape précédente de réduction ménagée d'un sulfinylimidate en aldimine n'ayant pas pu être mise au point. L'exploration de la réactivité des propargylsulfinamides oxygénés a par la suite permis de synthétiser des aminoesters et des éthers d'énols fonctionalisés ou encore d'accéder aux sulfonamides correspondants. Leur cyclisation par catalyse métallique a aussi été étudiée, conduisant à des sulfoximines cycliques jusqu'alors inconnus. En parallèle de ces travaux, une méthode générale et verte pour la synthèse d'imines et d'imidates sous irradiation micro-onde a été mise au point
The work reported in this manuscript mainly concerns the study of a synthetic strategy targetting the lycorine-type alkaloïds, compounds that are not well known but have shown interesting biological activities. In this context, a methodology concerning the nucleophilic addition of oxygenated acetylides on chiral Ellman's sulfinylimines has been developped, allowing the construction of oxygenated propargylamines xith an excellent diastereoselectivity. This reaction couldn't be applied to the total synthesis because of the fail of the precedent step of our synthteic plan, consisting in the reduction of sulfinylimidates into an aldimine. The reactivity of the oxygenated propargylsulfinamides has then been studied, allowing the preparation of aminoesters, functionalized enol ethers and sulfonyl protected propargylamines. Their cyclisation under metallic catlysis has been explored too, providing cyclic sulfoximines that had not been described before. In parallel, a general and green procedure for the synthesis of imines and imidates has been developped

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Gilligan, Ruth Elaine. "Copper-catalyzed C-H arylation : development of new methodology and its application to the total synthesis of staurosporinone". Thesis, University of Cambridge, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.607788.

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Chen, Chiliu. "Efforts toward the first enantioselective total synthesis of praziquantel and synthetic model studies on ecteinascidin 743 by novel aromatic C-H insertion methodology". [Tampa, Fla.] : University of South Florida, 2004. http://purl.fcla.edu/fcla/etd/SFE0000266.

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Gayraud, Oscar. "A journey into the total synthesis of Aspochalasins.From a two-phase strategy to peroxide rearrangements". Thesis, Institut polytechnique de Paris, 2020. http://www.theses.fr/2020IPPAX071.

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Pendant près de deux siècles, les chimistes de synthèse se sont intéressés à la reproduction des molécules présentes dans la nature. Les produits naturels sont une source presque infinie de défis synthétiques grâce à leur diversité structurale et leur complexité. Les chimistes ont utilisé diverses approches pour accéder à un grand nombre d'entre eux. De la synthèse totale ciblée à la synthèse totale diversifiée, les stratégies de synthèse des produits naturels ont évolué pour produire divers composés à partir d'intermédiaires communs en un court nombre d'étapes. De plus, les calculs DFT ont parfois été utilisés pour aider les chimistes à résoudre les problèmes rencontrés lors des synthèses totales. Le but de cette thèse était de réaliser la synthèse totale de substances naturelles de la famille des cytochalasines, tout en développant des méthodes de synthèse appropriées, en s'aidant des calculs DFT.Une approche en deux phases pour produire des produits naturels de la famille des aspochalasines, tels que la trichodermone et la trichodérone A, sera présentée. La construction du noyau principal utilisera une réaction de couplage croisé de Suzuki-Miyaura, une dihydroxylation asymétrique de Sharpless, un réarrangement d’Ireland-Claisen et une réaction de Diels-Alder. La synthèse du noyau isoindolone sera améliorée par des calculs DFT. Ensuite, une deuxième phase utilisant divers procédés d'oxydoréduction sera employée pour oxyder sélectivement un intermédiaire tétracyclique afin d'atteindre diverses aspochalasines.Les réarrangements de peroxydes organiques peuvent produire une grande variété de fonctions oxygénées. Lors des réarrangements de Criegee et de Hock, les peroxydes allyliques et benzyliques se réarrangent pour former des oxocarbéniums qui sont ensuite piégés par de l'eau pour former des dérivés carbonylés. De nouvelles méthodes seront présentées où divers nucléophiles seront utilisés pour piéger les oxocarbeniums et générer des éthers cycliques
Over almost two centuries, synthetic chemists have been interested in reproducing molecules found in Nature. Natural products are an almost infinite source of synthetic challenges by their complex structural diversity. Chemists have employed diverse approaches to access a vast number of them. From target-oriented synthesis to diverted total synthesis, strategies in natural product synthesis have evolved to produce diverse compounds from common intermediates in a short number of steps. Furthermore, DFT calculations have sometimes been used to assist chemists to solve problems encountered during total syntheses. The purpose of this thesis was the total synthesis of natural products of the cytochalasin family and the development of related synthetic methods, by using the strong support of DFT calculation.A two-phase approach to produce aspochalasin natural products, such as trichodermone and trichoderone A, will be presented. The construction of the main core will use Suzuki-Miyaura cross coupling reaction, Sharpless asymmetric dihydroxylation, Ireland-Claisen rearrangement and Diels-Alder cycloaddition. The Diels-Alder reaction towards the isoindolone core will be enhanced by DFT calculations. Then, a second phase using diverse redox processes will be employed to selectively oxidized tetracyclic intermediate to reach diverse aspochalasins.Organic peroxide rearrangements can produce a diverse variety of oxygenated functions. During the Criegee and Hock rearrangements, allylic and benzylic peroxides rearrange to form oxocarbenium species which are then trapped by water to form carbonyl derivatives. In this chapter, new methods will be presented where diverse nucleophiles will be used to trap oxocarbeniums and generate cyclic ethers

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Chatare, Vijay K. "METHODOLOGY AND NATURAL PRODUCT SYNTEHSIS: (A) NOVEL GLYCOSYL DONORS; (B) N-SULFINYL METALLODIENAMINES AND THEIR APPLICATION TO THE TOTAL SYNTHESIS OF (–)-ALBOCYCLINE". Diss., Temple University Libraries, 2017. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/456762.

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Chemistry
Ph.D.
My research involved in two different areas, development of novel glycosylation methodology and scope in oligosaccharide synthesis. A new scaffold for antibiotic development targeting the bacterial cell wall: Total synthesis of Albocycline and its analogs to see the mechanism of action in cell wall biosynthesis. Developed novel gem-dimethyl analogs of Fraser-Reid’s NPGs from 3,3-dimethyl 4-pentenol and 2,2-dimethyl 4-pentenol. These donors are stable toward acidic and basic conditions, which makes them step-efficient when compared to other glycosylating agents. The scope and reactivity of 3,3-dimethyl 4-pentenyl glycosides of glucose, mannose, galactose, and N-acetylglucosamine have been studied extensively for oligosaccharide synthesis. The donors are readily prepared from commercial starting materials and both glycosylation and hydrolysis yields are in the synthetically useful in oligosaccharide synthesis. NSMD methodology introduced a key step in albocycline synthesis, where (‒)-albocycline has great biological activity against “superbug” methicillin-resistant Staphylococcus aureus (MRSA). We hypothesize that albocycline inhibits the first committed step in bacterial cell wall biosynthesis. We have successfully completed two generation syntheses of albocycline. Vinylogous aldol on the left-handed fragment, aldehyde to get selectively up alcohol at the C-8 position using Davis-Ellman sulfinylimine chemistry and then oxidation with Davis oxaziridine to access requisite stereochemistry at C-4 alcohol followed by Horner-Wadsworth-Emmons to access seco-acid. Finally, a Keck macrolactonization reaction provided access to desired (‒)-Albocycline.
Temple University--Theses

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Corbin, Mathilde. "Formation de liaisons carbone-azote : application à la synthèse de benzazoles et de produits naturels marins bioactifs". Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS324/document.

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Ce manuscrit décrit des approches synthétiques de la benzosceptrine, pyrrole-2-aminoimidazole (P-2-AI) d'origine marine, via la création de liaisons C-N et une photodimérisation [2+2]. La synthèse totale de cette molécule originale et unique présente plusieurs challenges : la construction du motif benzo-bis-2-aminoimidazole et la synthèse régio- et stéréo-sélective du motif benzocyclobutanique. C’est dans ce but qu’une nouvelle méthodologie de diamination de 2-cyclohexènones par la 2-aminopyrimidine en présence du système catalytique fer/diiode/dioxygène a été mise au point et étendue aux 2-aminopyridines, chalcones et la chromone. L’application de cette méthode a permis d’achever la synthèse du motif benzo-bis-2-aminoimidazole de la benzosceptrine via l’installation de 4 liaisons C-N, en 6 étapes avec un rendement global de 28 % ; et d’explorer la réactivité de ce motif. La deuxième partie cyclobutanique a pu être réalisée grâce au développement d’une photodimérisation stéréo- et régio- sélective d’un acide (E)-3-(imidazo[1,2-a]pyrimidin-2-yl)acrylique. Bien que la synthèse totale de la benzosceptrine n’ait pas été achevée, ce travail nous a permis de préparer une chimiothèque de 50 dérivés simplifiés destinée aux évaluations biologiques. Ces évaluations en inhibition de kinases et en cytotoxicité ont mis en évidence un produit cytotoxique original et intéressant. Ce travail de recherche a donc permis d’avancer la synthèse de la benzosceptrine, de mettre au point une nouvelle méthode de diamination et de créer une chimiothèque de dérivés simplifiés d’un produit naturel
This manuscript describes synthetic approaches of benzosceptrin, a pyrrole-2-aminoimidazole (P-2-AI) isolated from a marine sponge, via C-N bond formation and a [2+2] photodimerization. Its synthesis presents the challenges of the benzo-bis-2-aminoimidazole moiety construction and the regio- and stereoselective synthesis of the benzocyclobutanic motif. With this objective, a new methodology of diamination of 2-cyclohexenones by 2-aminopyrimidine and 2-aminopyridines in the presence of the very simple iron/iodine/dioxygen catalytic system has been developed. It was also extended to chalcones and chromone. The application of this method allowed the synthesis of the benzo-bis-2-aminoimidazole moiety of benzosceptrin via the formation of 4 C-N bonds, in 6 steps in an overall yield of 28 % and to explore the reactivity of some intermediates. The second cyclobutanic moiety has been completed thanks to the development of a stereo- and regioselective photodimerization [2+2] of a (E)-3-(imidazo[1,2-a]pyrimidin-2-yl)acrylic acid. Although the total synthesis of benzosceptrin was not achieved, this work allowed the preparation of a chemical library of 50 simplified derivatives for biological evaluations. Those evaluations in kinases inhibition and cytotoxicity helped to highlight an original and interesting cytotoxic product. This research permitted to progress the synthesis of benzosceptrin, to develop a new method of diamination and to create a chemical library of simplified derivatives of a natural product

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Landaverry, Yakira Rodríguez. "Histidine-tyrosine side chain bonding : (1) Synthesis of cytochrome c oxidase active site model systems. (2) Synthetic methodology for the synthesis of the core histidine-tyrosine depeptide assembly of the natural products aciculitins A-C. Progress towards the total synthesis of psymberin: synthesis of the pyran core /". Diss., Digital Dissertations Database. Restricted to UC campuses, 2007. http://uclibs.org/PID/11984.

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Zhao, Senzhi. "NOVEL APPROACHES TO STRYCHNOS AND ASPIDOSPERMA ALKALOIDS". Diss., Temple University Libraries, 2015. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/367411.

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Chemistry
Ph.D.
All Strychnos and Aspidosperma alkaloids possess a core pyrrolo[2,3-d]carbazole ABCE tetracycle. In order to develop an efficient and divergent methodology for the synthesis of Strychnos alkaloids, a streamlined synthetic sequence to the ABCE tetracycle has been developed. It features a Mitsunobu activation of an N-hydroxyethyl gramine intermediate and subsequent intramolecular aza-Baylis-Hillman reaction. This method was first applied in the total synthesis of (±)-alstolucine B. Additional key steps in the synthesis included (1) chemoselective intermolecular and intramolecular Michael additions and (2) a Swern indoline oxidation. The second application of this method was in the first total synthesis of (-)-melotenine A, a novel rearranged Aspidosperma alkaloid with potent biological activity. Additional key steps in the synthesis included (1) a Piers annulation of a vinyl iodide and a methyl ketone to prepare the D ring and (2) a site-selective intermolecular vinylogous aldol reaction
Temple University--Theses

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Mondière, Aurélie. "Réactions multicomposants et applications : synthèse de cyclopent[b]indoles et pyrrolo[1,2-a]indoles : synthèse diastéréosélective de lignanes tétrahydrofuraniques trisubstitués". Phd thesis, Université Claude Bernard - Lyon I, 2010. http://tel.archives-ouvertes.fr/tel-00837814.

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Ce mémoire de thèse est composé de deux parties distinctes ayant comme thématique commune, les réactions multicomposants (MCR). Nous nous sommes intéressés dans un premier temps au développement d'une nouvelle MCR conduisant à des dérivés de l'indole, hétérocycle rencontré dans de nombreuses substances naturelles et composés biologiquement actifs. Nous avons ainsi mis au point un nouvelle méthodologie MCR séquentielle, rapide et efficace permettant d'accéder sélectivement, à partir des trois mêmes substrats (un précurseur indolique, un alcyne vrai et un accepteur de Michael) à deux familles de composés : les cyclopent[b]indoles ou les pyrrolo[1,2-a]indoles par une simple inversion de l'ordre des réactions. Puis dans un deuxième temps, nous avons élaboré une nouvelle synthèse totale diastéréosélective de lignanes tétrahydrofuraniques trisubstitués, connus pour leur abondance dans la nature et leurs propriétés biologiques très variées. Cette synthèse courte est composée de trois étapes clés : une réaction de cyclofonctionnalisation multicomposants palladocatalysée, une déméthoxycarboxylation -élimination utilisant des conditions de Krapcho modifiées et une réaction de type Hayashi-Miyaura permettant d'introduire le deuxième groupement aryle. Cette dernière réaction d'addition conjuguée a représenté le défi de cette synthèse et a donc fait l'objet d'une étude particulière sur un substrat modèle.

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Chen, Mingying. "A new methodology for the total synthesis of mitomycinoid FR900482". Thesis, 1998. http://hdl.handle.net/1911/17160.

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We describe the application of a novel ene-like reaction developed in our laboratory to the facile preparation of benzazocinone and benzazocenone intermediates of the type 3. Thus, ene-like reaction of 1 with 2-methoxypropene furnished adduct 2. This material underwent tandem intramolecular 1,3-dipolar azide cycloaddition and photolysis of the resulting triazoline to give 3. (DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE MAI) The newly developed avenue to these medium-ring heterocycles should be useful in a total synthesis of the antitumor agent, FR900482, 4. A synthesis of the highly substituted aldehyde 6, which could produce intermediates 5 suitable for the ultimate elaboration into 4 by the new chemistry, has also been developed.(DIAGRAM, TABLE OR GRAPHIC OMITTED...PLEASE SEE MAI)

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Kartika, Rendy. "Programs towards tetrahydropyran containing small macrolides of cyanobacterial origins synthetic methodology development and total synthesis /". 2008. http://etd.nd.edu/ETD-db/theses/available/etd-09122008-141650/.

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Thesis (Ph. D.)--University of Notre Dame, 2008.
Thesis directed by Richard E. Taylor for the Department of Chemistry and Biochemistry. "September 2008." Includes bibliographical references (leaves 569-605).

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Joshua, William Boyle. "A Unified Approach to Carbocyclic Frameworks: DTDA Sequences in Total Synthesis". Phd thesis, 2015. http://hdl.handle.net/1885/101992.

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[3]Dendralene is a small π-rich hydrocarbon that is capable of taking part in a wide range of chemical reactions, not least of which is the diene transmissive Diels–Alder (DTDA) reaction sequence. Unfortunately, the synthesis of this molecule relies on highly toxic and commercially unavailable intermediates, namely chloroprene. Chapter 1 of this thesis details a new synthetic approach to [3]dendralene via a double cross coupling reaction beginning with 1,1-‐‑ dichloroethylene and vinyl magnesium bromide. This work was extended to the synthesis of a variety of symmetrically substituted [3]dendralenes. Chapter 2 details the exploration of the Diels–Alder reactivity of [3]dendralene. While there has been some experimental work examining [3]dendralene in DTDA sequences, these have tended to focus on symmetrical and highly reactive dienophiles. This chapter describes the use of unsymmetrical dienophiles, which are either cyclic or acyclic in nature. This enables the synthesis of a range of polycyclic frameworks in just two steps. Through this methodology, the synthesis of bicyclic, linear tricyclic, angular tricyclic and angular tetracyclic structures is possible. The angular tetracyclic framework mentioned above is present in a number of natural products, including marine sponge derived compounds xestoquinone and halenaquinone. Chapter 3 presents a comprehensive review into previous syntheses of these two natural products as well as briefly examining work towards related natural products. Finally, Chapter 4 details our attempts to apply a DTDA reaction sequence beginning with [3]dendralene to the total synthesis of the natural product xestoquinone. [3]dendralene was reacted sequentially with two carbocyclic dienophiles before a series of functional group manipulations led to an advanced precursor of the targeted natural product.

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Gao, Xin active 2013. "Formation of C-C bonds via transfer hydrogenation : from methodology development to natural product synthesis". 2013. http://hdl.handle.net/2152/21412.

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Under the conditions of transfer hydrogenation employing ortho-cyclometallated iridium C,O-benzoate catalysts, selective silylallylation and CF₃-allylation were developed. In both cases, high levels of catalyst-directed enantioselectivity and diastereoselectivity were observed. Column chromatography was then tested as a new protocol to purify the iridium precatalyst; this single component precatalyst was proved to be more efficient to promote carbonyl crotylation reactions, both diastereo- and enantioselectivity were increased. Then, double asymmetric crotylation of 1,3-diols to deliver (pseudo-)C₂-symmetric adducts with exceptional level of enantioselectivity was devised. Implementation of this methodology and other hydrogenative C-C bond formations proved to be effective means for the preparation of two known polypropionate natural product fragments of C19-C25 of scytophycin C, C19-C27 of rifamycin S and the total synthesis of 6-deoxyerythronolide B.
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Allan, Kevin McCormack. "Development of Versatile Strategies for Aryne Annulation: Applications in Methodology and Natural Product Total Synthesis". Thesis, 2010. https://thesis.library.caltech.edu/5744/2/THESIS_-_Kevin_M_Allan_-_Vol_1.pdf.

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Since the elucidation of its structure in 1953, benzyne has been the focus of intense interest within the chemical community. Due to an unusually high degree of ring strain, benzyne displays reactivity uncharacteristic of common alkynes, including a tendency to react under mild metal-free conditions. This reactivity is exploited in the development of three novel methods for the synthesis of heterocyclic structures.

The first synthetic methodology includes two orthogonal annulation reactions taking place between functionalized enamines and arynes. The substitution at the nitrogen atom of the enamine determines the path of reactivity. Carbamates undergo a formal [3 + 2] cycloaddition with arynes to give rise to indolines, while amides undergo a formal [4 + 2] cycloaddition and dehydration to form isoquinolines. The latter reaction is applied to a three-step synthesis of the antispasmotic pavine alkaloid, papaverine.

This isoquinoline-forming aryne annulation reaction is further employed in a concise asymmetric total synthesis of the tetrahydroisoquinoline antitumor antibiotic, (–)-quinocarcin. In addition to this key transformation, the synthetic route features an auxiliary-mediated diastereoselective dipolar cycloaddition to set the absolute stereochemistry and a novel two-step reduction to form the tetrahydroisoquinoline. In total, this strategy has enabled the shortest total synthesis of this important alkaloid reported to date.

The second methodology involves the synthesis of 3-hydroxyisoquinolines and 2-hydroxy-1,4-naphthoquinones from β-ketoesters using an aryne acyl-alkylation reaction in combination with an in-situ condensation. This technology enables the preparation of highly functionalized polyaromatic ring systems in two steps from readily available carboxylic acid starting materials. As a demonstration of its utility, this method is employed in a rapid synthesis of the P,N-ligand, QUINAP.

Finally, the development of a pair of three-component coupling reactions between arynes, isocyanides, and a third relay species is described. Phenyl esters and quinones lead to iminoisobenzofurans, while alkynes furnish iminoindenones. Procedures for the subsequent hydrolysis of these products are provided, thereby giving access to synthetically useful ortho-ketobenzamide and indenone compounds.

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Maifeld, Sarah Virginia. "I. Progress toward the total synthesis of Guanacastepene A : II. Silyloxyl-tethered methodology development : new applications in enyne metathesis and hydrosilylation chemistry /". 2006. http://catalog.hathitrust.org/api/volumes/oclc/84542196.html.

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Wengryniuk, Sarah Elizabeth. "Regioselective Asymmetric a,a-Bisalkylation of Ketones via N-Amino Cyclic Carbamate Chiral Auxiliaries: Methodology Development and Application to the Total Synthesis of both (+)- and (-)-Stigmolone and Apratoxin D". Diss., 2012. http://hdl.handle.net/10161/5574.

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The α-alkylation of ketones is a transformation of central importance to organic synthesis. Our lab recently introduced the N-amino cyclic carbamate (ACC) chiral auxiliaries for asymmetric ketone α-alkylation. ACCs provide significant advantages over existing asymmetric ketone alkylation methods as they are easy to introduce, both deprotonation and alkylation can be run at relatively mild temperatures, stereoselectivity of alkylation is excellent and auxiliary removal is facile. A unique feature of ACCs is their ability to control the regioselectivity of deprotonation through what we have termed Complex Induced Syn-Deprotonation. In what follows, we describe several projects relating to the development and synthetic application of ACCs.

An optimized synthesis of our most successful ACC auxiliary was developed, including an improved method for the formation of the key N-N hydrazide bond.

A detailed mechanistic investigation of four ACC auxiliaries was conducted, examining the regio- and stereoselectivity of the alkylations at the level of the ACC hydrazone. This work culminated in a theoretical study of ACC auxiliaries, conducted through a collaboration with the Houk Group at UCLA.

We also describe the use of ACCs in the development of the first method for the regiocontrolled asymmetric α,α-bisalkylation of ketones. The method proceeds in excellent yield and with >99:1 diastereoselectivity. This method was also extended to the asymmetric α,α,α',α'-tetraalkylation of ketones, enabled by the development of a mild, epimerization-free LDA-mediated isomerization of the α,α-bisalkylated ACC hydrazones.

Additionally, we discuss three synthetic applications of the ACC α,α-bisalkylation methodology. We report an asymmetric formal synthesis of (+)- and (-)-stigmolone, as well as two approaches to the polyketide fragment of the novel cyclic depsipeptide apratoxin D, which have led to the completion of the first asymmetric total synthesis of apratoxin D.

Dissertation

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Brekan, Jonathan Alan. "Application of carbon-hydrogen activation/Cope rearrangement methodology towards the total syntheses of Pseudopterosin, Elisabethatriene and Vinigrol". 2008. http://proquest.umi.com/pqdweb?did=1594481381&sid=4&Fmt=2&clientId=39334&RQT=309&VName=PQD.

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Thesis (Ph.D.)--State University of New York at Buffalo, 2008.
Title from PDF title page (viewed on Jan. 15, 2009) Available through UMI ProQuest Digital Dissertations. Thesis adviser: Davies, Huw M. Includes bibliographical references.

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